Immune Tolerance Mediated by Negative Costimulatory Molecules

描述（由申请方提供）：维持对自身组织免疫耐受的分子机制尚未完全了解。T细胞活化和耐受性由先天免疫系统调节，重要的是通过共刺激分子。T细胞在缺乏阳性共刺激（CD 28和ICOS）的情况下活化导致其耐受性和无反应性，这是静息状态下T细胞外周耐受性的主要机制。另一方面，已经发现其他共刺激途径，如CTLA 4和PD-1抑制T细胞活化。因此，B7共刺激分子家族的成员，通过其在CD 28家族中的受体，在决定T细胞活化或自身耐受性中发挥重要作用。我们最近在小鼠中鉴定并鉴定了两个新的B7样抑制分子- B7-H3和B7 S1。阻断抗它们的抗体可加重体内实验性变态反应性脑脊髓炎（EAE）疾病。BTNL 2是我们最近表征的亲酪蛋白分子，其结合活化的T细胞并抑制其增殖。尽管近年来发现了大量的T细胞抑制剂，但其在免疫耐受调节中的特异性生理功能尚未得到很好的理解。在本申请中，我们提出比较B7-H3、B7 S1和BTNL 2在免疫耐受中的作用，特别是通过分析它们在外周耐受和自身免疫性疾病模型的发病机制中的作用。首先，我们描述了B7-H3和B7 S1在外周耐受机制中的功能。其次，我们将研究B7- H3和B7 S1在自身免疫性疾病模型中的作用。最后，我们将研究BTNL 2的表达和功能。这些研究将大大提高我们对这些新的共刺激分子在免疫耐受调节中的理解。

DESCRIPTION (provided by applicant): The molecular mechanisms whereby the immune tolerance to self tissues is maintained are not well understood. T cell activation and tolerance is regulated by the innate immune system, importantly through co-stimulatory molecules. Activation of T cells in the absence of positive cositmulation (CD28 and ICOS) results in their tolerance and anergy, which is the main mechanism for peripheral tolerance of T cells in resting states. On the other hand, other costimulatory pathways, such as CTLA4 and PD-1 have been discovered to inhibit T cell activation. Thus, members of the B7 costimulator family, through their receptors in the CD28 family, play essential roles in determining T cell activation or self-tolerance. We have recently identified and characterized two new B7-like inhibitory molecules in mouse- B7-H3 and B7S1. Blocking antibodies against them exacerbated experimental allergic encephalomyelitis (EAE) disease in vivo. BTNL2 is a butyrophilin molecule we recently characterized that binds to activated T cell and inhibits their proliferation. Despite a large number of T cell inhibitors identified in the recent years, their specific physiological function in regulation of immune tolerance has not been well understood. In this application, we propose to compare the actions by B7-H3, B7S1 and BTNL2 in immune tolerance, specifically by analyzing their roles in peripheral tolerance and in pathogenesis of autoimmune disease models. First, we characterize the function of B7-H3 and B7S1 in peripheral tolerance mechanisms. Secondly, we will study the roles of B7- H3 and B7S1 in autoimmune disease models. Lastly, we will examine the expression and function of BTNL2. These studies will greatly improve our understanding of these novel costimulatory molecules in immune tolerance regulation.